Bone marrow cells as a source of neurons for brain and spinal cord repair

Abstract

Bone marrow stromal cells (BMSC) differentiate into neuron-like phenotypes in vitro and in vivo, engrafted into normal or denervated rat striatum. The BMSC did not remain localized to the site of the graft, but migrated throughout the brain and integrated into specific brain regions in various architectonic patterns. The most orderly integration of BMSC was in the laminar distribution of cerebellar Purkinje cells, where the BMSC-derived cells took on the Purkinje phenotype. The BMSC exhibited site-dependent differentiation and expressed several neuronal markers including neuron-specific nuclear protein, tyrosine hydroxylase and calbindin. BMSC can be used to target specific brain nuclei in strategies of neural repair and gene therapy.

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 60 / 084,533, filed May 7, 1998; U.S. Provisional Application No. 60 / 112,979, filed Dec. 17, 1998; and U.S. Provisional Application No. 60 / 129,684 filed Apr. 16, 1999.[0002] 1. Field of Use[0003] This application relates to methods of culturing bone marrow cells such that they express neuronal phenotype for use in transplantation.[0004] 2. Background Information[0005] Neurobiologists have long considered the neurons in the adult brain to be like a precious nest egg: a legacy that dwindles with time and illness and is difficult if not impossible to rebuild. Parkinson's and Alzheimer's are examples of neurodegenerative diseases whose cures await scientists overcoming the difficulty of rebuilding neurons in the human adult brain. Parkinson's disease (PD), is a disorder of middle or late life, with very gradual progression and a prolonged course. HARRISON'S PRINCIPLES OF INTERNAL MEDICINE, Vol. 2, 23d ed., Ed. ...

AI Technical Summary

Problems solved by technology

Neurobiologists have long considered the neurons in the adult brain to be like a precious nest egg: a legacy that dwindles with time and illness and is difficult if not impossible to rebuild.

Although the modem treatment of PD is more successful than any that was available before the introduction of levodopa, including stereotactic surgery, there are still many problems.

Underlying much of the difficulty undoubtedly is the fact that none of these therapeutic measures has an effect on the underlying disease process, which consists of neuronal degeneration.

Ultimately, a point seems to be reached where pharmacology can no longer compensate for the loss of basal ganglia dopamine.

At present there are palliative treatments but no means to restore function.

Purkinje cells are permanently lost, resulting in ataxia.

Even if the patient is permanently cured of the cancer, their ability to function may be profoundly disabled by the loss of Purkinje cells.

Strokes also result in neuronal degeneration and loss of functional synapses.

The experimental replacement of neurons by direct grafting of fetal tissue into the brain has been accomplished in small numbers of patients in several research universities (including our University of South Florida); but so far, the experimental grafting of human fetal neurons has been limited by scarcity of appropriate tissue sources, logistic problems, legal and ethical constraints, and poor survival of grafted neurons in the human host brain.

Most of the data suggest that the fibroblasts are of local origin, but the issue has not been resolved and is still being examined.

Even though the multipotential properties of MSCs have been recognized for several decades, there are surprisingly large gaps in our information about the cells themselves.

The isolation of adequate numbers of HSCs requires large volumes of marrow (1 liter or more), and the cells are difficult to expand in culture.

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